This invention relates to a novel class of monocyclic xcex2-lactam compounds and compositions comprising a single, 4-membered azetidinone ring, which exhibit wide-ranging antibacterial activity, wherein the N1 nitrogen atom of the azetidinone ring is bonded to sulfur but is not sulfonated. Specifically, compounds are disclosed that inhibit growth of diverse strains of bacteria wherein substitutions at positions C3 and C4 of the azetidinone ring, and at the sulfur atom, produce antibacterial agents of varying bacterial specificity and efficacy. Additionally, the invention relates to methods for the synthesis of the aforementioned compounds.
The clinical use of antibiotics in the 20th century has substantially decreased morbidity from bacterial infections. The early success of penicillin was extended by various sulfonamide drugs developed in the 1930s, and subsequently by a xe2x80x9cgoldenxe2x80x9d period of discovery, between 1945 and 1970, during which a wide array of highly effective agents were discovered and developed. See: Chopra, I., Hodgson, J., Metcalf, B. and Poste, G. xe2x80x9cThe Search for Antimicrobial Agents Effective against Bacteria Resistant to Multiple Antibioticsxe2x80x9d (1997) Antimicrobial Agents and Chemotherapy 41:497-503.
However, since the 1980s the introduction of new antibiotics has slowed, and, concurrently, there has been an alarming increase in bacterial resistance to existing agents that now constitutes a serious threat to public health. See: Brown, A. G. (1987) xe2x80x9cDiscovery and Development of New xcex2-Lactum Antibioticsxe2x80x9d Pure and Appl. Chem. 59:475-484. Hospitals, nursing homes and infant day care centers have become breeding grounds for the most tenacious drug-resistant pathogens. See: xe2x80x9cFrontiers in Biotechnologyxe2x80x9d (1994) Science 264:359-393. There has been an alarming rise in drug resistant staphylococci, enterococci, streptococci, and pneumococci infections, and an increase in tuberculosis, influenza and sepsis.
For several decades, xcex2-lactam antibiotics have been widely used to control bacterial infections. Since the discovery of penicillin, countless numbers of analogues have been prepared and tested (see for example: U.S. Pat. No. 5,142,039 to Blaszczak et al., and U.S. Pat. No. 5,338,861 to Botts et al.), and a variety of successful modifications have been made to the five-membered ring, including (1) replacement of the sulfur atom with carbon or oxygen, (2) oxidation of the sulfur to the sulfoxide or sulfone, (3) enlargement to a larger ring, (4) incorporation of unsaturation, (5) attachment of additional fused rings, and (6) removal of the five membered ring. As a result, new xcex2-lactam ring systems have been introduced, including the penems, cephalosporins, carbapenems, oxapenems, oxacephams, as well as monocyclic, spirocyclic , and multicyclic xcex2-lactams. In the case of monocyclic xcex2-lactams (see: Sykes, R. B., Cimarusti, C. M., Bonner, D. P., Bush, K., Floyd, D. M., Georgopapadakou, N. H., Koster, W. H., Trejo, W. H. and Wells, J. S. (1981) xe2x80x9cMonocyclic xcex2-Lactam Antibiotics Produced by Bacteriaxe2x80x9d Nature 291:489-490), which directly relates to the present invention, removal of the five-membered ring leaves a four-membered xcex2-lactam ring, the structural core of which is 2-azetidinone (1): 
Monocyclic antibiotics successfully developed by derivatization of this core structure include the monobactams (see: Slusarchyk, W. A., Dejneka, T., Gordon, E. M., Weaver, E. R. and Koster, W. H. xe2x80x9cMonobactams: Ring Activating N-1-Substituents in Monocyclic xcex2-Lactam Antibioticsxe2x80x9d (1984) Heterocycles 21:191-209.), which have 2-oxoazetidine sulfonic acid as their characteristic structure. A key feature of the monobactams is the activation of the xcex2-lactam ring towards nucleophilic attack by bacterial transpeptidases that is caused by the electron-withdrawing potential of the sulfonated nitrogen atom. Alternative activating groups for monobactam derivatives have been discovered, including phosphate, phosphonate, and analogues in which a spacer atom is interposed between the ring nitrogen and activating group (see: Breuer, H., Straub, H., Treuner, U. D., Drossard, J.-M., Hxc3x6hn, H. and Lindner, K. R. xe2x80x9c[(2-oxo-1-azetidinyl)oxy]acetic acids: a new class of synthetic monobactamsxe2x80x9d (1985) J. Antibiotics 38:813-818, and Slusarchyk, W. A., Dejneka, T., Gordon, E. M., Weaver, E. R. and Koster, W. H. xe2x80x9cMonobactams: Ring Activating N-1-Substituents in Monocyclic xcex2-Lactam Antibioticsxe2x80x9d (1984) Heterocycles 21:191-209).
The primary targets of xcex2-lactams are the penicillin binding proteins, a group of bacterial proteins that mediate the final step of bacterial cell wall biosynthesis in which a terminal alanine-alanine linkage of a peptidoglycan strand is cleaved by an active site serine and crosslinked to another peptidoglycan fragment, thus strengthening the bacterial cell wall. Penicillin interrupts this crosslinking step by acylating the serine with its reactive xcex2-lactam ring. Following acylation, ring opening results in further chemical fragmentations that are deleterious to the enzyme. Also among the penicillin binding proteins are the xcex2-lactamases: enzymes that degrade xcex2-lactams. Clavulinic acid targets these enzymes, and is therefore useful in conjunction with established penicillins in combination therapies for combating certain resistant strains of bacteria. See: Chopra, I., Hodgson, J., Metcalf, B. and Poste, G. xe2x80x9cThe Search for Antimicrobial Agents Effective against Bacteria Resistant to Multiple Antibioticsxe2x80x9d (1997) Antimicrobial Agents and Chemotherapy 41:497-503.
There is a clear need for new antibacterial agents to combat pathogenic bacteria that have become resistant to current antibiotics. Towards this end, a novel class of derivatized, N-thiolated, monocyclic xcex2-lactams have been developed in the present invention, that exhibit strong antibacterial activity against a wide variety of species and strains.
The invention comprises a novel class of monocyclic xcex2-lactam antibacterial and antibiotic agents, herein termed N-1 thiolated monolactams, of the general structure: 
independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl; X is H, C or O;and n=0 to 3.
It is an object of the present invention to provide these compounds, including their salts, hydrates, and in combinations with suitable pharmaceutical carriers, as antibacterial and antibiotic agents.
It is a further object of this invention to provide such compounds, wherein R4 and R5 are hydrogen, and xe2x80x94C(R1)3 is methyl or benzyl (xe2x80x94CH2Ph).
It is yet a further object of the invention to provide antibacterial and antibiotic agents with varying bacterial strain specificities and efficacies, by the expedient means of varying substituents of the 2-azetidinone ring, including but not limited to nitrogen (N-1) thiomethyl or thiobenzyl moieties, and substitutions at the C3 and C4 positions.
In another embodiment, it is a further object of this invention to provide methods for inhibiting the growth of bacteria by administering the compounds of the present invention, and to provide methods for the treatment of bacterial infections of a patient, in which one or more doses of an effective amount of the compounds and compositions of the present invention are administered to a patient.
It is yet a further objective of the present invention to provide compounds and compositions suitable for the treatment of gonorrhea.
The present invention confers numerous advantages over the compounds of the prior art, including the following: ease of synthesis, whereby compounds with diverse substituents may be synthesized and tested for antibacterial and antibiotic activity; the invention provides novel antibacterial and antibiotic agents to which bacterial pathogens have not yet acquired resistance; and the invention provides novel compounds for the treatment of increasingly common and resistant diseases such as gonorrhea. Surprisingly, the inventors have found that antibacterial and antibiotic activities can be obtained in compounds that do not possess traditional activating groups attached to the sulfur, as required for activity in conventional monobactams which contain, for example, sulfone groups. The inventors have also surprisingly discovered that derivatization of structure (2) at the positions indicated by the R1-5 and X, results in compounds exhibiting different specificities for different bacterial pathogens, in a manner that is currently not possible to predict a priori. This aspect is therefore an unobvious benefit of the present invention. The present invention fullfills a dire need in that novel antibacterial compounds are urgently required as bacterial pathogens increasingly acquire immunity towards the present arsenal of antibiotics.
The term xe2x80x9cN-1 thiolated monolactamxe2x80x9d is used herein to refer to a monocyclic 4-membered beta-lactam compound comprising an 4-azetidinone ring in which the ring nitrogen (N-1) atom is covalently bonded to a sulfur that is covalently bonded to a carbon-centered moiety, and which may be further modified as described herein. Specifically, referring now to compound (2), X may be a hydrogen (in which case, n is preferably zero), or a carbon atom (in which case n is preferably 3), or an oxygen atom (in which case, n is preferably 1), and R2 may be any substituent as herein defined. Similarly, R1 and R3-5 may be independently any substituent as herein defined except that the compounds 1-thiomethyl-3-methoxy-4-phenylethynyl-2-oxoazetidine and 1-thiomethyl-3-methoxy-4-(O-acetyl)phenylethynyl-2-oxoazetidine are specifically excluded from the definition of N-1 thiolated monolactam as used herein.
Thus, in preferred embodiments, R1 is hydrogen or benzyl, and in most preferred embodiments R1 is hydrogen. Substituents comprising xe2x80x94X(R2)n are preferably methoxy and hydrogen, and most preferably methoxy. R3 may be alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl. Preferred R3 substituents are phenylethynyl, acetoxy, 1-propenyl, ortho-chlorophenyl, ortho-nitrophenyl, 2-thiophene, or S,S-dioxo-thiophene. R4 and R5 may be independently alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl groups. In preferred embodiments, R4 and R5 are H.
The following definitions are used, unless otherwise described. Halo is fluoro, chloro, bromo, or iodo. xe2x80x9cAlkyl,xe2x80x9d xe2x80x9calkoxy,xe2x80x9d etc. denote both straight and branched groups; but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to. xe2x80x9cArylxe2x80x9d denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. xe2x80x9cHeteroarylxe2x80x9d encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Rx) wherein Rx is absent or is hydrogen, oxo, alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
It will be appreciated by those skilled in the art that compounds of the invention having one or more chiral center(s) may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis, from optically-active starting materials. by chiral synthesis, or by chromatographic separation using a chiral stationary phase), and how to determine antibacterial activity using the tests described herein, or using other tests which are well known in the art. The preferred absolute configuration for compounds of the invention is that shown in formula (2) above.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Specifically, xe2x80x9calkylxe2x80x9d can include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl; xe2x80x9calkenylxe2x80x9d can include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl; 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, 1-tridecenyl, 2-tridecenyl, 3-tridecenyl, 4-tridecenyl, 5-tridecenyl, 6-tridecenyl, 7-tridecenyl, 8-tridecenyl, 9-tridecenyl, 10-tridecenyl, 11-tridecenyl, 12-tridecenyl, 1-tetradecenyl, 2-tetradecenyl, 3-tetradecenyl, 4-tetradecenyl, 5-tetradecenyl, 6-tetradecenyl 7-tetradecenyl, 8-tetradecenyl, 9-tetradecenyl, 10-tetradecenyl, 11-tetradecenyl, 12-tetradecenyl, 13-tetradecenyl, 1-pentadecenyl, 2-pentadecenyl, 3-pentadecenyl, 4-pentadecenyl, 5-pentadecenyl, 6-pentadecenyl, 7-pentadecenyl, 8-pentadecenyl, 9-pentadecenyl, 10-pentadecenyl, 11-pentadecenyl, 12-pentadecenyl, 13-pentadecenyl, 14-pentadecenyl; xe2x80x9calkoxyxe2x80x9d can include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexoxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, or pentadecyloxy; xe2x80x9calkanoylxe2x80x9d can include acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, or pentadecanoyl; xe2x80x9ccycloalkylxe2x80x9d can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. xe2x80x9cArylxe2x80x9d can include phenyl, indenyl, 5,6,7,8-tetrahydronaphthyl, or naphthyl. xe2x80x9cHeteroarylxe2x80x9d can include furyl, imidazolyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, or quinolyl (or its N-oxide).
Specific independent values for R1-5, include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(C1-C10)alkyl, (C3-C8)cycloalkyl(C1-C15)alkenyl, (C3-C8)cycloalkyl(C1-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, or (C1-C15)alkanoyloxy; wherein R1 is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C1-C15)alkyl, (C2-C15)alkenyl, (C2-C15)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl (C1-C15)alkyl, (C3-C8)cycloalkyl(C2-C15)alkenyl, (C3-C8)cycloalkyl(C2-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, (C1-C15)alkanoyloxy, C (xe2x95x90O)ORa, C(xe2x95x90O)NRb Rc, OC (xe2x95x90O) ORa, OC (xe2x95x90O) NRb Rc, and NRe Rf.
Another specific value for R1-5, includes aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl, (C1-C10)alkoxy, (C1-C10)alkanoyl, (C2-C10)alkanoyloxy, C(xe2x95x90O)ORa, C(xe2x95x90O)NRb Rc, or NRc Rf.
Other specific values for R1-5, include independently phenyl or naphthyl, optionally substituted with a substituent selected from the group consisting of halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C1-C10)alkoxy, (C1-C10)alkanoyl, (C2-C10)alkanoyloxy, C(xe2x95x90O)ORa, C(xe2x95x90O)NRb Rc, or NRe Rf.
Still other specific values for R1-5, include aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C2-C6)alkenyl, heteroaryl(C2-C6)alkenyl, aryl(C2-C6)alkynyl, or heteroaryl(C2-C6)alkynyl; wherein any aryl or heteroaryl is optionally substituted with halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C1-C15)alkyl, (C2-C15)alkenyl, (C2-C15)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C15)alkyl, (C3-C8)cycloalkylxe2x80x94(C2-C15)alkenyl, C3-C8)cycloalkyl(C2-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, (C1-C15)alkanoyloxy, C(xe2x95x90O)ORa, C(xe2x95x90O)NRb Rc, or NRe Rf.
The compounds of the present invention exhibit broad antibacterial activity against several families of bacteria in the Gram-negative and Gram-positive range, and against beta-lactamase producing strains. Because of their powerful antibacterial properties, the present compounds may also be used to supplement feed for animals.
In addition, the compounds of the present invention that exhibit antibacterial activity may also be used as medicaments, and also as substances for preserving inorganic and organic materials, especially organic materials of all kinds, for example polymers, lubricants, paints, fibers, leather, paper, timber, foodstuffs, and water.
The compounds of the present invention may also be used to prevent, alleviate, or cure diseases caused by pathogens whose growth is inhibited by these compounds. The instant compounds are particularly active against bacteria and bacteria-like microorganisms. They are therefore suitable for use in human and veterinary medicine, for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens.
As an illustrative, but not limiting, list of pathogens, the following pathogenic microorganisms are possible targets of the compounds of the present invention. Micrococcaceae, such as Staphylococci, for example Staphylococcus aureus, Staph. epidermidis and Staph. aerogenes; Lactobacteriaceae, such as Streptococci, for example Streptococcus pyogenes; Neisseriaceae, such as Neisseriae, for example Neisseria gonorrhoeae (Gonococci); Corynebacteriaceae, such as Corynebacteria; Listeria bacteria; Erysipelothrix bacteria; Kurthia bacteria; Enterobacteriaceae, such as Escherichia bacteria of the Coli group; Klebsiella bacteria; Erwiniae; Serratia; Proteae bacteria; Providencia bacteria; Salmonella bacteria; Shigella; Pseudomonadaceae; Aeromonas bacteria; Spirillaceae, such as Vibrio bacteria; Spirillum bacteria; Parvobacteriaseae; Brucella bacteria; Bordetella bacteria; Moraxella bacteria; Fusiform bacteria; Bacillaceae; Clostridia; Spirochaetaceae; Treponema bacteria; and Leptospira bacteria.
Examples which may be cited of diseases which can be prevented, alleviated, or cured by the compounds of the present invention are: diseases of the respiratory passages and of the pharyngeal cavity; otitis; pharyngitis; pneumonia; peritonitis; pyelonephritis; cystitis; endocarditis; systemic infections; and bronchitis.
The compounds of the present invention include all hydrates and salts that can be prepared by those of skill in the art. Under conditions where the compounds of the present invention are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
The compounds of the present invention can be formulated as pharmaceutical compositions and administered to a patient, such as a human patient, in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient""s diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its slats can be prepared in water or other suitable solvent, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
For topical administration, the present compounds may be applied in pure-form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are disclosed in Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Useful dosages of the compounds of the present invention can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
Generally, the concentration of the compound(s) of formula (I) in a liquid composition, such as a lotion, will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
Accordingly, the invention includes a pharmaceutical composition comprising a compound of the present invention as described above; or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions adapted for oral, topical or parenteral administration, comprising an amount of one or more compounds effective to treat a bacterial infection, are a preferred embodiment of the invention.
The present invention provides a novel class of monocyclic substituted xcex2-lactams, specifically termed N-1 thiolated monolactams as defined herein. The present invention will therefore be fully understood by one of skill in the art by reference to the following embodiments, examples, and claims.